The worldwide health problem created by malaria has been made more difficult by the spread of drug- resistant parasites. This project initiates preclinical development of one or more candidate(s) from an innovative new class of potent antimalarials designed to overcome drug resistance. We have developed an orally available and inexpensive class of novel drugs that act against both chloroquine-resistant and chloroquine-sensitive malaria. A small set of carefully-selected candidates will be advanced through preclinical testing, leading to the selection of a single drug for a pre-Investigational New Drug meeting with the Food and Drug Administration. With guidance from the Food and Drug Administration, pharmacokinetics, pharmacodynamics, pharmacology, and toxicity evaluations will be performed in both rats and monkeys in phase II of this work. The overall goal will be completion of preclinical studies leading to approval of the Investigative New Drug (IND) application for a drug to be used in a Phase-1 human clinical trial. PUBLIC HEALTH RELEVANCE: Malaria is a disease that infects about half a billion people annually, and kills nearly one million, most of whom are children or pregnant women. The impact of malaria is increasing, partly because the parasite that causes malaria has evolved into strains that are resistant to the best current drugs for treating the disease. This project involves preclinical evaluation of novel drugs designed to circumvent this resistance, paving the way toward approval for human clinical trials. The drug candidates show promising results in early studies, and are designed to be inexpensive as well as safe for all target groups, including pregnant women and children.